Summary of Work: An important class of at-risk motifs (ARMs) that can lead to human genome instability involves interspersed repetitive sequences. These can be a source of large chromosomal rearrangements in somatic and germ cells. We are investigating mechanisms of recombination between repeat ARMs, impact of divergence, organization and size of repeats, environmental agent effects as well as genetic controls in the yeast Saccharomyces cerevisiae. This organism serves as a model genetic system for changes in human cells. The most abundant class of interspersed repeats in the human genome, Alus, comprise approximately 10% of total DNA. The average sequence divergence is 85% which might be a barrier to rearrangement. We developed a novel system in yeast to address the ability of homologous and diverged Alus that are organized in motifs present in the human genome to stimulate recombination. Of particular interest is the inverted Alu repeat motif which is found in the human genome, since we have shown that a palindrome formed between 1.0 kb URA3 genes can increase recombination approximately 20,000-fold. To investigate i) the potential for inverted Alu-repeats to stimulate genome instability and ii) the effect of sequence divergence, we constructed a set of quasipalindrome inserts (12 bp between the Alu repeats) with varying levels of identity. The 300 bp inverted Alu repeats with greater than 99% identity increased recombination nearly 1000-fold over that of either direct repeats or unique DNA. 95%, 85% and 76% identical IRs exhibited 100-, 5- fold and no increase, respectively. Surprisingly, mismatch repair defects do not affect recombination stimulation. Thus, even diverged inverted Alus can induce genetic rearrangements. This model system is being used to investigate the many factors that could contribute to repeat stimulated instability including mismatch and recombinational repair, replication and environmental agents. To quantitatively assess repeat ARMs in the human genome, we are analyzing the human genome data base for the presence of closely space Alu repeats. This will be extended to other repeats.